The Significance of Serum Interleukin-8 in Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

Backgrounds
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is closely related to disease mortality. Systemic inflammation is considered to be involved in the pathogenesis of AECOPD. The current study aimed to investigate the clinical significance of the classic chemokine interleukin (IL)-8 in serum during AECOPD.


Materials and Methods
In this current cross sectional, observational study, 50 patients with AECOPD, 25 patients with stable COPD and 25 healthy nonsmokers as the control group were selected. Clinical characteristics and spirometry data were collected. All patients were classified as grade 1-4 based on forced expiratory volume in 1 second (FEV1) after bronchodilation according to the GOLD severity classification and were divided into frequent exacerbation (FE) group (≥2 times/year) and non-frequent exacerbation (NFE) group (<1 time/year) according to acute exacerbation (AE) times in the previous 12 months before the visit. The serum IL-8, IL-6, tumor necrosis factor (TNF)-α, and superoxide dismutase levels were measured by the enzyme-linked immunosorbent assay technique.


Results
Serum IL-8 levels increased sequentially from controls [9.45 pg/mL (ranged: 6.85-38.4)], to stable [51.60 pg/mL (ranged: 22.4-131.1)], and exacerbation stage [129 pg/mL (ranged: 57.7-374)]. The level of serum IL-8 was significant higher in patients with FE than that of patients with NFE (209.0 pg/mL (ranged: 115-472) vs 65.6 pg/mL (ranged: 11.2-149.3), P=0.008). A receiver operating characteristics curve (ROC) generated to evaluate IL-8, IL-6, and TNF-α levels to discriminate between patients with and without exacerbation showed that the total area under the curve (AUC) was 0.71 (95% confidence interval (CI): 0.5764-0.8381; P=0.003), 0.54 (95%CI: 0.4048-0.6943; P=0.54), and 0.52 (95%CI: 0.3912-0.6656; P= 0.7).


Conclusion
Serum IL-8 is a sensitive, easy-to-measure, and inexpensive biomarker to give an indication of the course of COPD during exacerbation, and is a target to be explored further as a predictor to distinguish the patients prone to exacerbation.


Study design
In the current cross sectional, observational study, a total of 50 patients with AECOPD and 25 patients with stable COPD were selected from the patients admitted to Thoracic Society (ATS) spirometry standards (7). Airflow obstruction was defined by a forced expiratory volume in one second to forced vital capacity (FEV1/FVC) ratio of <70% following the administration of 200 μg of inhaled salbutamol. The lung function grade of COPD was classified based on FEV1 as a predicted percentage (8). The 25 controls included asymptomatic never smokers who did not demonstrate any airflow limitation by spirometry. All subjects (cases and controls) were ethnically similar males.
Smoking history was defined using pack-years.
Exacerbations were defined as increase in any or all of the three major symptoms (dyspnea, sputum volume, and sputum color) from day to day routine in accordance with the definition of Burge and Wedzicha (9). All patients with AECOPD were classified based on GOLD severity classification as 1(≥80%), 2 (≥50% and <80), 3(≥30% and All the supernatants were stored at -70°С until assay.

Statistical analysis
All data were analyzed using Graphpad Prism 5.0 or Sigmaplot 12.0 for windows. Continuous variables were expressed as mean ± standard deviation and median with interquartile range. Serum IL-8, IL-6, and TNF-α levels were transformed to a natural logarithm to mitigate the influence of extreme outliers. Differences between the two groups were evaluated by the Mann-Whitney U-test.
Intergroup comparison of the three groups was conducted by the nonparametric Kruskal-Wallis test. Relationships between the serum levels of IL-8 and clinical variables were determined by univariate linear regression.
Comparison between IL-8, IL-6, and TNF-α was performed by ROC (receiver operating characteristics curve) construction and the area under the curve (AUC) measurement. A P-value <0.05 was considered the level of significance.

Clinical characteristics
Totally, 100 male subjects including 50 patients with exacerbation of COPD, 25 patients with clinically stable COPD, and 25 healthy controls were included in the study.
Their baseline characteristics are shown in Table 1

Variables associated with serum IL-8 in AECOPD
In patients with AECOPD, significant correlations were observed between serum IL-8 and blood eosinophil counts, blood eosinophil percentage, the change rate of predicted FEV1, DLCO, and SOD levels in Table 2.       In the current study, IL-6 and TNF-α were two wellknown traditional systemic inflammatory mediators of COPD exacerbation; the finding was also reported by most previous studies (13). The comparison between IL-8 and the above two mediators in specificity and sensitivity of AECOPD was not reported before. The current study compared these three mediators of AECOPD and for the first time proved that serum IL-8 is more sensitive than IL-6 and TNF-α in Chinese population.  The current study does not allow any conclusions whether or not the relationship between IL-8 and the studied parameters was causal; however, it encourages further mechanistic studies to better understand the issue.
According to the results of the current study, it can be concluded that serum IL-8 can be a sensitive, easy-tomeasure, and inexpensive biomarker to give an indication of the course of COPD during an exacerbation; and it is a target to be explored further as a predictor to distinguish the patients with COPD prone to exacerbation to implement individualized treatment and improve the disease outcome.